Wound healing is as much about opportunity (Gk. Karios) and sequence (Gk. Chronos). The sequential healing responses involve concerted responses of cells of various lineages along with both soluble (cytokines and growth factors) and insoluble (matrix composition and topology) that are precisely coordinated for ultimate healing. This motivated the current scoping review to examine the biological relevance and utility of current in vitro models of wound healing, focusing on specific cellular responses.
Recent Advances:
We examined PubMed, Web of Science, and EBSCO of Science for the years 2020–2025, using keywords in vitro wound healing and individual cell type, namely epithelial cells, keratinocytes, fibroblasts, macrophages, platelets, and endothelial cells. This identified 126 relevant studies were selected and categorized by healing stage, cell types, and prototypical biological responses such as proliferation, migration, and lineage-specific functions.
Critical Issues:
This analysis outlined the utility of a temporal framework to organize current in vitro models as acute—initial, early and late, and chronic—delayed. Existing two-dimensional and three-dimensional models focus on platelet function (hemostasis), neutrophil or macrophage chemotaxis and phagocytosis (inflammation), epithelium (closure), fibroblast (matrix synthesis, contraction), and endothelial (angiogenesis). While these models provide key insights into specific phases, cell functions, and molecular mechanisms, they do not fully replicate the integrated, multiorgan processes of wound healing observed in vivo.
Future Directions:
Sequential combinations of these models lend themselves to the advances in artificial intelligence, machine learning, and robotic automation that are integral to developing prognostic and therapeutic wound care agents.
MartinP, ParkhurstSM. Parallels between tissue repair and embryo morphogenesis. Development, 2004; 131(13):3021–3034.
2.
DvorakHF. Tumors: Wounds that do not heal-redux. Cancer Immunol Res, 2015; 3(1):1–11.
3.
HendrixMJC, SeftorEA, SeftorREB, et al.Reprogramming metastatic tumour cells with embryonic microenvironments. Nat Rev Cancer, 2007; 7(4):246–255.
4.
EmingSA, MartinP, Tomic-CanicM. Wound repair and regeneration: Mechanisms, signaling, and translation. Sci Transl Med, 2014; 6(265):265sr6.
5.
GurtnerGC, WernerS, BarrandonY, et al.Wound repair and regeneration. Nature, 2008; 453(7193):314–321.
6.
SenCK. Wound healing essentials: Let there be oxygen. Wound Repair Regen, 2009; 17(1):1–18.
7.
SindrilaruA, PetersT, WieschalkaS, et al.An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J Clin Invest, 2011; 121(3):985–997.
8.
RoderoMP, KhosrotehraniK. Skin wound healing modulation by macrophages. Int J Clin Exp Pathol, 2010; 3(7):643–653.
9.
MartinP, D’SouzaD, MartinJ, et al.Wound healing in the PU.1 null mouse–tissue repair is not dependent on inflammatory cells. Curr Biol, 2003; 13(13):1122–1128.
10.
FinnsonKW, AranyPR, PhilipA. Transforming growth factor beta signaling in cutaneous wound healing: Lessons learned from animal studies. Adv Wound Care (New Rochelle), 2013; 2(5):225–237.
11.
HinzB. Formation and function of the myofibroblast during tissue repair. J Invest Dermatol, 2007; 127(3):526–537.
12.
AranyPR, FlandersKC, KobayashiT, et al.Smad3 deficiency alters key structural elements of the extracellular matrix and mechanotransduction of wound closure. Proc Natl Acad Sci U S A, 2006; 103(24):9250–9255.
13.
RodriguesM, KosaricN, BonhamCA, et al.Wound healing: A cellular perspective. Physiol Rev, 2019; 99(1):665–706.
14.
TottoliEM, DoratiR, GentaI, et al.Skin wound healing process and new emerging technologies for skin wound care and regeneration. Pharmaceutics, 2020; 12(8):735.
15.
WilkinsonHN, HardmanMJ. Wound healing: Cellular mechanisms and pathological outcomes. Open Biol, 2020; 10(9):200223.
16.
BeamAL, KohaneIS. Big data and machine learning in health care. JAMA, 2018; 319(13):1317–1318.
17.
NussbaumSR, CarterMJ, FifeCE, et al.An economic evaluation of the impact, cost, and medicare policy implications of chronic nonhealing wounds. Value Health, 2018; 21(1):27–32.
18.
LeskovecNK, HuljevD, MatohM. Wounds in vascular and metabolic diseases. Acta Med Croatica, 2012; 66(Suppl 1):93–97.
19.
FrykbergRG, BanksJ. Challenges in the treatment of chronic wounds. Adv Wound Care (New Rochelle), 2015; 4(9):560–582.
20.
SchultzGS, et al.Principles of wound healing. In: Mechanisms of vascular disease: A reference book for vascular specialists. (FitridgeR, ThompsonM, eds.) University of Adelaide Press: Adelaide, AU; 2011. pp. 1–30.
21.
NuutilaK, ErikssonE. Moist wound healing with commonly available dressings. Adv Wound Care (New Rochelle), 2021; 10(12):685–698.
22.
NagleSM, StevensKA, WilbrahamSC. Wound Assessment. StatPearls: Treasure Island, FL: 2025.
23.
AtherS, HardingKG, TateSJ. 1—Wound management and dressings, in Advanced Textiles for Wound Care (Second Edition),RajendranS., Editor. 2019, Woodhead Publishing. pp. 1–22.
24.
JaulE. Assessment and management of pressure ulcers in the elderly: Current strategies. Drugs Aging, 2010; 27(4):311–325.
25.
RaziyevaK, KimY, ZharkinbekovZ, et al.Immunology of acute and chronic wound healing. Biomolecules, 2021; 11(5):700.
26.
HuntM, TorresM, Bachar-WikstromE, et al.Cellular and molecular roles of reactive oxygen species in wound healing. Commun Biol, 2024; 7(1):1534.
27.
Cano SanchezM, LancelS, BoulangerE, et al.Targeting oxidative stress and mitochondrial dysfunction in the treatment of impaired wound healing: A systematic review. Antioxidants (Basel), 2018; 7(8):98.
28.
TangD, KangR, CoyneCB, et al.PAMPs and DAMPs: Signal 0s that spur autophagy and immunity. Immunol Rev, 2012; 249(1):158–175.
29.
NeryNM, SetúbalSS, BoenoCN, et al.Bothrops erythromelas venom and its action on isolated murine macrophages. Toxicon, 2020; 185:156–163.
IngleRA, CarstensM, DenbyKJ. PAMP recognition and the plant-pathogen arms race. Bioessays, 2006; 28(9):880–889.
32.
JanewayCAJr, MedzhitovR. Innate immune recognition. Annu Rev Immunol, 2002; 20:197–216.
33.
SchremlS, SzeimiesRM, PrantlL, et al.Oxygen in acute and chronic wound healing. Br J Dermatol, 2010; 163(2):257–268.
34.
PowerG, MooreZ, O’ConnorT. Measurement of pH, exudate composition and temperature in wound healing: A systematic review. J Wound Care, 2017; 26(7):381–397.
35.
SchneiderLA, KorberA, GrabbeS, et al.Influence of pH on wound-healing: A new perspective for wound-therapy? Arch Dermatol Res, 2007; 298(9):413–420.
36.
ManchandaM, TorresM, InuossaF, et al.Metabolic reprogramming and reliance in human skin wound healing. J Invest Dermatol, 2023; 143(10):2039–2051 e10.
37.
WilgusTA, RoyS, McDanielJC. Neutrophils and wound repair: Positive actions and negative reactions. Adv Wound Care (New Rochelle), 2013; 2(7):379–388.
38.
CastanheiraFVS, KubesP. Neutrophils and NETs in modulating acute and chronic inflammation. Blood, 2019; 133(20):2178–2185.
39.
PastarI, StojadinovicO, YinNC, et al.Epithelialization in Wound Healing: A Comprehensive Review. Adv Wound Care (New Rochelle), 2014; 3(7):445–464.
40.
RosinczukJ, TaradajJ, DymarekR, et al.Mechanoregulation of wound healing and skin homeostasis. Biomed Res Int, 2016:3943481.
41.
NurdenAT. Qualitative disorders of platelets and megakaryocytes. J Thromb Haemost, 2005; 3(8):1773–1782.
42.
AlessiMC, SiéP, PayrastreB. Strengths and weaknesses of light transmission aggregometry in diagnosing hereditary platelet function disorders. J Clin Med, 2020; 9(3):763.
43.
GrambowE, SorgH, SorgCGG, et al.Experimental models to study skin wound healing with a focus on angiogenesis. Med Sci (Basel), 2021; 9(3):55.
LacyP. Mechanisms of degranulation in neutrophils. Allergy Asthma Clin Immunol, 2006; 2(3):98–108.
46.
BrinkmannV, ZychlinskyA. Neutrophil extracellular traps: Is immunity the second function of chromatin? J Cell Biol, 2012; 198(5):773–783.
47.
PapayannopoulosV. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol, 2018; 18(2):134–147.
48.
KerriganAM, BrownGD. C-type lectins and phagocytosis. Immunobiology, 2009; 214(7):562–575.
49.
MargrafA, LeyK, ZarbockA. Neutrophil recruitment: From model systems to tissue-specific patterns. Trends Immunol, 2019; 40(7):613–634.
50.
KimYW, ByzovaTV. Oxidative stress in angiogenesis and vascular disease. Blood, 2014; 123(5):625–631.
51.
AhnJ, OhkK, WonJ, et al.Modeling of three-dimensional innervated epidermal like-layer in a microfluidic chip-based coculture system. Nat Commun, 2023; 14(1):1488.
52.
Shabestani MonfaredG, ErtlP, RothbauerM. An on-chip wound healing assay fabricated by xurography for evaluation of dermal fibroblast cell migration and wound closure. Sci Rep, 2020; 10(1):16192.
53.
DongY, WangZ. ROS-scavenging materials for skin wound healing: Advancements and applications. Front Bioeng Biotechnol, 2023; 11:1304835.
54.
MedzhitovR. Origin and physiological roles of inflammation. Nature, 2008; 454(7203):428–435.
55.
KrzyszczykP, SchlossR, PalmerA, et al.The role of macrophages in acute and chronic wound healing and interventions to promote pro-wound healing phenotypes. Front Physiol, 2018; 9:419.
56.
KimSY, NairMG. Macrophages in wound healing: Activation and plasticity. Immunol Cell Biol, 2019; 97(3):258–267.
57.
StrizovaZ, BenesovaI, BartoliniR, et al.M1/M2 macrophages and their overlaps—myth or reality? Clin Sci (Lond), 2023; 137(15):1067–1093.
58.
MantovaniA, SicaA, LocatiM. Macrophage Polarization Comes of Age. Immunity, 2005; 23(4):344–346.
59.
SicaA, MantovaniA. Macrophage plasticity and polarization: In vivo veritas. J Clin Invest, 2012; 122(3):787–795.
60.
MantovaniA, SicaA, SozzaniS, et al.The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol, 2004; 25(12):677–686.
61.
MantovaniA, BiswasSK, GaldieroMR, et al.Macrophage plasticity and polarization in tissue repair and remodeling. J Pathol, 2013; 229(2):176–185.
62.
DaleyJM, BrancatoSK, ThomayAA, et al.The phenotype of murine wound macrophages. J Leukoc Biol, 2010; 87(1):59–67.
63.
ShookB, XiaoE, KumamotoY, et al.CD301b+ macrophages are essential for effective skin wound healing. J Invest Dermatol, 2016; 136(9):1885–1891.
64.
AshcroftGS, JeongM-J, AshworthJJ, et al.Tumor necrosis factor-alpha (TNF-alpha) is a therapeutic target for impaired cutaneous wound healing. Wound Repair Regen, 2012; 20(1):38–49.
65.
RoderoMP, HodgsonSS, HollierB, et al.Reduced Il17a expression distinguishes a Ly6c(lo)MHCII(hi) macrophage population promoting wound healing. J Invest Dermatol, 2013; 133(3):783–792.
66.
KingA, BalajiS, LeLD, et al.Regenerative wound healing: The role of interleukin-10. Adv Wound Care (New Rochelle), 2014; 3(4):315–323.
67.
OkizakiS-I, ItoY, HosonoK, et al.Suppressed recruitment of alternatively activated macrophages reduces TGF-beta1 and impairs wound healing in streptozotocin-induced diabetic mice. Biomed Pharmacother, 2015; 70:317–325.
68.
EmingSA, WynnTA, MartinP. Inflammation and metabolism in tissue repair and regeneration. Science, 2017; 356(6342):1026–1030.
69.
WetzlerC, KämpferH, StallmeyerB, et al.Large and sustained induction of chemokines during impaired wound healing in the genetically diabetic mouse: Prolonged persistence of neutrophils and macrophages during the late phase of repair. J Invest Dermatol, 2000; 115(2):245–253.
70.
StroberW. Trypan blue exclusion test of cell viability. Curr Protoc Immunol, 2015; 111:A3.B.1–A3.B.3.
71.
LiangCC, ParkAY, GuanJL. In vitro scratch assay: A convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc, 2007; 2(2):329–333.
72.
BoniakowskiAE, KimballAS, JacobsBN, et al.Macrophage-mediated inflammation in normal and diabetic wound healing. J Immunol, 2017; 199(1):17–24.
73.
GriffoniC, NeidhartB, YangK, et al.In vitro skin culture media influence the viability and inflammatory response of primary macrophages. Sci Rep, 2021; 11(1):7070.
74.
KnoedlerS, KnoedlerL, Kauke-NavarroM, et al.Regulatory T cells in skin regeneration and wound healing. Mil Med Res, 2023; 10(1):49.
75.
BoothbyIC, CohenJN, RosenblumMD. Regulatory T cells in skin injury: At the crossroads of tolerance and tissue repair. Sci Immunol, 2020; 5(47):eaaz9631.
76.
SunL, SuY, JiaoA, et al.T cells in health and disease. Signal Transduct Target Ther, 2023; 8(1):235.
77.
ShortWD, WangX, KeswaniSG. The role of t lymphocytes in cutaneous scarring. Adv Wound Care (New Rochelle), 2022; 11(3):121–131.
78.
HofmannE, FinkJ, PignetA-L, et al.Human in vitro skin models for wound healing and wound healing disorders. Biomedicines, 2023; 11(4):1056.
79.
WernerS, GroseR. Regulation of wound healing by growth factors and cytokines. Physiol Rev, 2003; 83(3):835–870.
80.
MartinP. Wound healing–aiming for perfect skin regeneration. Science, 1997; 276(5309):75–81.
PatelGK, WilsonCH, HardingKG, et al.Numerous keratinocyte subtypes involved in wound re-epithelialization. J Invest Dermatol, 2006; 126(2):497–502.
83.
RognoniE, WattFM. Skin cell heterogeneity in development, wound healing, and cancer. Trends Cell Biol, 2018; 28(9):709–722.
84.
MartinP, LewisJ. Actin cables and epidermal movement in embryonic wound healing. Nature, 1992; 360(6400):179–183.
85.
LaplanteAF, GermainL, AugerFA, et al.Mechanisms of wound reepithelialization: Hints from a tissue-engineered reconstructed skin to long-standing questions. Faseb J, 2001; 15(13):2377–2389.
86.
UsuiML, UnderwoodRA, MansbridgeJN, et al.Morphological evidence for the role of suprabasal keratinocytes in wound reepithelialization. Wound Repair Regen, 2005; 13(5):468–479.
87.
SafferlingK, SütterlinT, WestphalK, et al.Wound healing revised: A novel reepithelialization mechanism revealed by in vitro and in silico models. J Cell Biol, 2013; 203(4):691–709.
88.
ScholzenT, GerdesJ. The Ki-67 protein: From the known and the unknown. J Cell Physiol, 2000; 182(3):311–322.
89.
BellE, EhrlichHP, ButtleDJ, et al.Living tissue formed in vitro and accepted as skin-equivalent tissue of full thickness. Science, 1981; 211(4486):1052–1054.
90.
StarkH-J, BoehnkeK, MiranceaN, et al.Epidermal homeostasis in long-term scaffold-enforced skin equivalents. J Investig Dermatol Symp Proc, 2006; 11(1):93–105.
91.
SrinivasanB, KolliAR, EschMB, et al.TEER measurement techniques for in vitro barrier model systems. J Lab Autom, 2015; 20(2):107–126.
92.
ZhangM, ZhangC, LiZ, et al.Advances in 3D skin bioprinting for wound healing and disease modeling. Regen Biomater, 2023; 10:rbac105.
93.
TomasekJJ, GabbianiG, HinzB, et al.Myofibroblasts and mechano-regulation of connective tissue remodeling. Nat Rev Mol Cell Biol, 2002; 3(5):349–363.
94.
DesmouliereA. Factors influencing myofibroblast differentiation during wound healing and fibrosis. Cell Biol Int, 1995; 19(5):471–476.
95.
DriskellRR, LichtenbergerBM, HosteE, et al.Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature, 2013; 504(7479):277–281.
96.
RognoniE, PiscoAO, HiratsukaT, et al.Fibroblast state switching orchestrates dermal maturation and wound healing. Mol Syst Biol, 2018; 14(8):e8174.
97.
BensaT, TekkelaS, RognoniE. Skin fibroblast functional heterogeneity in health and disease. J Pathol, 2023; 260(5):609–620.
98.
PlikusMV, WangX, SinhaS, et al.Fibroblasts: Origins, definitions, and functions in health and disease. Cell, 2021; 184(15):3852–3872.
99.
BellE, IvarssonB, MerrillC. Production of a tissue-like structure by contraction of collagen lattices by human fibroblasts of different proliferative potential in vitro. Proc Natl Acad Sci U S A, 1979; 76(3):1274–1278.
100.
ClarkRA. Fibronectin matrix deposition and fibronectin receptor expression in healing and normal skin. J Invest Dermatol, 1990; 94(6 Suppl):128S–134S.
KimD-H, LipkeEA, KimP, et al.Nanoscale cues regulate the structure and function of macroscopic cardiac tissue constructs. Proc Natl Acad Sci U S A, 2010; 107(2):565–570.
103.
WallIB, MoseleyR, BairdDM, et al.Fibroblast dysfunction is a key factor in the non-healing of chronic venous leg ulcers. J Invest Dermatol, 2008; 128(10):2526–2540.
104.
SapudomJ, ElGindiM, ArnouxM, et al.Fibroblast differentiation and matrix remodeling impaired under simulated microgravity in 3D cell culture model. Int J Mol Sci, 2021; 22(21):11911.
105.
ZhaoF, ZhangM, NizamogluM, et al.Fibroblast alignment and matrix remodeling induced by a stiffness gradient in a skin-derived extracellular matrix hydrogel. Acta Biomater, 2024; 182:67–80.
BarrientosS, StojadinovicO, GolinkoMS, et al.Growth factors and cytokines in wound healing. Wound Repair Regen, 2008; 16(5):585–601.
108.
CarmelietP. Angiogenesis in life, disease and medicine. Nature, 2005; 438(7070):932–936.
109.
FalangaV. Wound healing and its impairment in the diabetic foot. Lancet, 2005; 366(9498):1736–1743.
110.
ArnaoutovaI, GeorgeJ, KleinmanHK, et al.The endothelial cell tube formation assay on basement membrane turns 20: State of the science and the art. Angiogenesis, 2009; 12(3):267–274.
111.
KorffT, AugustinHG. Tensional forces in fibrillar extracellular matrices control directional capillary sprouting. J Cell Sci, 1999; 112(Pt 19):3249–3258.
112.
KimS, LeeH, ChungM, et al.Engineering of functional, perfusable 3D microvascular networks on a chip. Lab Chip, 2013; 13(8):1489–1500.
113.
BlackAF, BerthodF, L’heureuxN, et al.In vitro reconstruction of a human capillary-like network in a tissue-engineered skin equivalent. Faseb J, 1998; 12(13):1331–1340.
114.
JohnsonKE, WilgusTA. Vascular endothelial growth factor and angiogenesis in the regulation of cutaneous wound repair. Adv Wound Care (New Rochelle), 2014; 3(10):647–661.
115.
SarianMN, ZulkefliN, Che ZainMS, et al.A review with updated perspectives on in vitro and in vivo wound healing models. Turk J Biol, 2023; 47(4):236–246.
116.
RibattiD, TammaR. A revisited concept. Tumors: Wounds that do not heal. Crit Rev Oncol Hematol, 2018; 128:65–69.
117.
DvorakHF. Tumors: Wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med, 1986; 315(26):1650–1659.
118.
JorgensenSN, SandersJR. Mathematical models of wound healing and closure: A comprehensive review. Med Biol Eng Comput, 2016; 54(9):1297–1316.
119.
RobsonMC, HillDP, WoodskeME, et al.Wound healing trajectories as predictors of effectiveness of therapeutic agents. Arch Surg, 2000; 135(7):773–777.
120.
SherrattJA, DallonJC. Theoretical models of wound healing: Past successes and future challenges. C R Biol, 2002; 325(5):557–564.
121.
ZiraldoC, MiQ, AnG, et al.Computational modeling of inflammation and wound healing. Adv Wound Care (New Rochelle), 2013; 2(9):527–537.
122.
WongSL, DemersM, MartinodK, et al.Diabetes primes neutrophils to undergo NETosis, which impairs wound healing. Nat Med, 2015; 21(7):815–819.
123.
KimM-H, LiuW, BorjessonDL, et al.Dynamics of neutrophil infiltration during cutaneous wound healing and infection using fluorescence imaging. J Invest Dermatol, 2008; 128(7):1812–1820.
124.
OmarA, WrightJB, SchultzG, et al.Microbial biofilms and chronic wounds. Microorganisms, 2017; 5(1):9.
125.
LootsMA, LammeEN, ZeegelaarJ, et al.Differences in cellular infiltrate and extracellular matrix of chronic diabetic and venous ulcers versus acute wounds. J Invest Dermatol, 1998; 111(5):850–857.
126.
HardingKG, MorrisHL, PatelGK. Science, medicine and the future: Healing chronic wounds. BMJ, 2002; 324(7330):160–163.
127.
SinghD, RaiV, AgrawalDK. Regulation of collagen i and collagen iii in tissue injury and regeneration. Cardiol Cardiovasc Med, 2023; 7(1):5–16.
128.
XueM, JacksonCJ. Extracellular matrix reorganization during wound healing and its impact on abnormal scarring. Adv Wound Care (New Rochelle), 2015; 4(3):119–136.
129.
DarbyIA, LaverdetB, BontéF, et al.Fibroblasts and myofibroblasts in wound healing. Clin Cosmet Investig Dermatol, 2014; 7:301–311.
130.
RittieL. Cellular mechanisms of skin repair in humans and other mammals. J Cell Commun Signal, 2016; 10(2):103–120.
131.
YangH, ZhangX, XueB. New insights into the role of cellular senescence and chronic wounds. Front Endocrinol (Lausanne), 2024; 15:1400462.
132.
LabibA, WintersR. Complex Wound Management. StatPearls: Treasure Island, FL: 2025.
133.
MuneerPMA, PfisterBJ, HaorahJ, et al.Role of matrix metalloproteinases in the pathogenesis of traumatic brain injury. Mol Neurobiol, 2016; 53(9):6106–6123.
134.
SmithJ, RaiV. Novel factors regulating proliferation, migration, and differentiation of fibroblasts, keratinocytes, and vascular smooth muscle cells during wound healing. Biomedicines, 2024; 12(9):1939.
135.
TrengoveNJ, StaceyMC, MacAuleyS, et al.Analysis of the acute and chronic wound environments: The role of proteases and their inhibitors. Wound Repair Regen, 1999; 7(6):442–452.
136.
HeussenC, DowdleEB. Electrophoretic analysis of plasminogen activators in polyacrylamide gels containing sodium dodecyl sulfate and copolymerized substrates. Anal Biochem, 1980; 102(1):196–202.
BrewK, NagaseH. The tissue inhibitors of metalloproteinases (TIMPs): An ancient family with structural and functional diversity. Biochim Biophys Acta, 2010; 1803(1):55–71.
139.
NwomehBC, YagerDR, CohenIK. Physiology of the chronic wound. Clin Plast Surg, 1998; 25(3):341–356.
140.
CaleyMP, MartinsVL, O’TooleEA. Metalloproteinases and wound healing. Adv Wound Care (New Rochelle), 2015; 4(4):225–234.
141.
National Academies of Sciences, E. Medicine. Microphysiological Systems: Bridging Human and Animal Research. In: Proceedings of a Workshop—in Brief. The National Academies Press: Washington, DC; 2021; p. 10.
142.
RasouliM, SafariF. Principles of Indirect Co-culture Method Using Transwell. In: Stem Cell Niche: Methods and Protocols (TurksenK., ed.) Springer US: New York, NY; 2025; pp. 257–263.
143.
HaydenPJ, HarbellJW. Special review series on 3D organotypic culture models: Introduction and historical perspective. In Vitro Cell Dev Biol Anim, 2021; 57(2):95–103.
144.
LeachT, GandhiU, ReevesKD, et al.Development of a novel air–liquid interface airway tissue equivalent model for in vitro respiratory modeling studies. Sci Rep, 2023; 13(1):10137.
145.
van RietS, NinaberDK, MikkersHMM, et al.In vitro modelling of alveolar repair at the air-liquid interface using alveolar epithelial cells derived from human induced pluripotent stem cells. Sci Rep, 2020; 10(1):5499.
146.
SharmaS, KishenA. Microengineered diabetic wound-on-a-chip model for emulating chronic wound dynamics. Lab Chip, 2025; 25(23):6290–6305.
147.
RisueñoI, ValenciaL, JorcanoJL, et al.Skin-on-a-chip models: General overview and future perspectives. APL Bioeng, 2021; 5(3):e030901.
PhanDTT, WangX, CraverBM, et al.A vascularized and perfused organ-on-a-chip platform for large-scale drug screening applications. Lab Chip, 2017; 17(3):511–520.
150.
DealHE, BrownAC, DanieleMA. Microphysiological systems for the modeling of wound healing and evaluation of pro-healing therapies. J Mater Chem B, 2020; 8(32):7062–7075.
151.
MoriN, MorimotoY, TakeuchiS. Skin integrated with perfusable vascular channels on a chip. Biomaterials, 2017; 116:48–56.
152.
GurevichDB, SevernCE, TwomeyC, et al.Live imaging of wound angiogenesis reveals macrophage orchestrated vessel sprouting and regression. Embo J, 2018; 37(13):e97786.
153.
IyerK, ChenZ, GanapaT, et al.Keratinocyte migration in a three-dimensional in vitro wound healing model co-cultured with fibroblasts. Tissue Eng Regen Med, 2018; 15(6):721–733.
154.
SchremlS, MeierRJ, KirschbaumM, et al.Luminescent dual sensors reveal extracellular pH-gradients and hypoxia on chronic wounds that disrupt epidermal repair. Theranostics, 2014; 4(7):721–735.
155.
ChenH, ChengY, TianJ, et al.Dissolved oxygen from microalgae-gel patch promotes chronic wound healing in diabetes. Sci Adv, 2020; 6(20):eaba4311.
156.
GengK, MaX, JiangZ, et al.High glucose-induced STING activation inhibits diabetic wound healing through promoting M1 polarization of macrophages. Cell Death Discov, 2023; 9(1):136.
157.
WangX, YangC, YuY, et al.In situ 3D bioprinting living photosynthetic scaffolds for autotrophic wound healing. Research, 2022; 2022.
158.
ZhaoY, ZhaoY, XuB, et al.Microenvironmental dynamics of diabetic wounds and insights for hydrogel-based therapeutics. J Tissue Eng, 2024; 15:20417314241253290.
159.
GaneshK, SinhaM, Mathew-SteinerSS, et al.Chronic wound biofilm model. Adv Wound Care (New Rochelle), 2015; 4(7):382–388.
160.
DibanF, Di LodovicoS, Di FermoP, et al.Biofilms in chronic wound infections: Innovative antimicrobial approaches using the in vitro Lubbock chronic wound biofilm model. Int J Mol Sci, 2023; 24(2):1004.
161.
CavalloI, SivoriF, MastrofrancescoA, et al.Bacterial biofilm in chronic wounds and possible therapeutic approaches. Biology (Basel), 2024; 13(2):109.
162.
Cárdenas-CalderónC, Veloso-GiménezV, GonzálezT, et al.Development of an implantable three-dimensional model of a functional pathogenic multispecies biofilm to study infected wounds. Sci Rep, 2022; 12(1):21846.
163.
ZhaoG, UsuiML, LippmanSI, et al.Biofilms and inflammation in chronic wounds. Adv Wound Care (New Rochelle), 2013; 2(7):389–399.
164.
VoDK, TrinhKTL. Advances in wearable biosensors for wound healing and infection monitoring. Biosensors (Basel), 2025; 15(3):139.
165.
BattagliaTM, MassonJ-F, SierksMR, et al.Quantification of cytokines involved in wound healing using surface plasmon resonance. Anal Chem, 2005; 77(21):7016–7023.
166.
PakshirP, NoskovicovaN, LodygaM, et al.The myofibroblast at a glance. J Cell Sci, 2020; 133(13):jcs227900.
167.
HinzB. Matrix mechanics and regulation of the fibroblast phenotype. Periodontol 2000, 2013; 63(1):14–28.
168.
GodboutC, Follonier CastellaL, SmithEA, et al.The mechanical environment modulates intracellular calcium oscillation activities of myofibroblasts. PLoS One, 2013; 8(5):e64560.
169.
GhandourS, Rodriguez AlvarezAA, CieriIF, et al.Using machine learning models to predict post-revascularization thrombosis in PAD. Front Artif Intell, 2025; 8:1540503.
170.
CuiJ, WangM, LinC, et al.Exploring machine learning strategies for single-cell transcriptomic analysis in wound healing. Burns Trauma, 2025; 13:tkaf032.
171.
HarriotAD, WardCW, KimDH. Microphysiological systems to advance human pathophysiology and translational medicine. J Appl Physiol (1985), 2024; 137(5):1494–1501.
172.
AjalikRE, AlencheryRG, CognettiJS, et al.Human Organ-on-a-Chip microphysiological systems to model musculoskeletal pathologies and accelerate therapeutic discovery. Front Bioeng Biotechnol, 2022; 10:846230.
173.
MaassC, DallasM, LaBargeME, et al.Establishing quasi-steady state operations of microphysiological systems (MPS) using tissue-specific metabolic dependencies. Sci Rep, 2018; 8(1):8015.
174.
StefanelliA, ZahiaS, ChanelG, et al.Developing an AI-powered wound assessment tool: A methodological approach to data collection and model optimization. BMC Med Inform Decis Mak, 2025; 25(1):297.
175.
Al-JuhaniA, DesokyR, AbdullahA, et al.Machine learning in predicting wound healing and limb salvage outcomes following lower limb revascularization: A systematic review of prognostic accuracy. Cureus, 2025; 17(7):e88568.
176.
CaiX, LiW, ShiW, et al.Modeling epithelial wound closure dynamics with AI: A comparative study across cell types. Regen Ther, 2025; 30:860–867.
177.
PamiesD, EkertJ, ZurichM-G, et al.Recommendations on fit-for-purpose criteria to establish quality management for microphysiological systems and for monitoring their reproducibility. Stem Cell Reports, 2024; 19(5):604–617.
178.
ChoKJ, et al.Microfluidic system based high throughput toxicity and efficacy screening system for eyedrops in ocular surface experiments. Investigative Ophthalmology & Visual Science, 2016; 57(12):3877.
179.
SchmidtK, LermD, SchmidtA, et al.Automated high-throughput live cell monitoring of scratch wound closure. Biomed Eng Comput Biol, 2024; 15:11795972241295619.
180.
VerseyZ, da Cruz NizerWS, RussellE, et al.Biofilm-innate immune interface: Contribution to chronic wound formation. Front Immunol, 2021; 12:648554.
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